Tumor specific CD8+ cytotoxic T lymphocytes (CTL) appear to constitute an important effector limb of the anti-tumor immune response as indicated by animal model studies (Greenberg, 1991, Adv. Immunol. 49: 281). Therefore, tumor specific Ag recognized by CTL are likely to function as tumor rejection Ag, capable of inducing protective immunity in vivo.
MHC class I and class II molecules, constituitively expressed on APC, are responsible for the presentation of non-overlapping Ag-derived peptides to CD8+ CTL and CD4+ helper T cells (Th), respectively (Rothbard et al., 1987, Nature 326: 881; Babbitt et al., 1985, Nature 317: 359). CTL recognize class I molecules containing peptidic fragments of intracellular proteins that have been transported into endoplasmic reticulum prior to their transfer to the MHC molecule (Germain, 1995, Ann. NY Acad. Sci. 754:114; Heemels & Ploegh, 1995, Annu. Rev. Biochem. 64:463), while the bulk of class II complexed peptides presented to Th cells are degradation products of exogenous or cell surface proteins that enter the biosynthetic pathway of class II molecules via endocytosis and a subsequent fusion with lysosomes (Cresswell, 1994, Annu. Rev. Immunol. 12: 259). This dichotomy of Ag presentation explains why Ag-specific CD8+ CTL are generated most effectively against intracellular Ag, or when the extracellular Ag are delivered into the cytosol. Since intact proteins in the extracellular medium do not ordinarily penetrate into the cytosol, soluble proteins typically fail to elicit CTL responses (Braciale et al., 1987, Immunol. Rev. 98: 95).
It is therefore desirable to provide a method for eliciting CTL responses against soluble proteins.